Abstract
The lack of a functional Foxp3 transcription factor and regulatory T (Treg) cells causes lethal, CD4+ T cell-driven autoimmune diseases in scurfy (SF) mice and humans. Recent studies have shown that adenosine A2A receptor activation limits inflammation and tissue damage, thereby playing an anti-inflammatory role. However, the role of the adenosine A2A receptor in the development of disease in SF mice remains unclear. Using a genetic approach, we found that adenosine A2A receptor deletion in SF mice (SF) does not affect early life events, the development of a lymphoproliferative disorder, or hyper-production of pro-inflammatory cytokines seen in the Treg-deficiency state. As shown previously, Lactobacillus reuteri DSM 17938 treatment prolonged survival and reduced multiorgan inflammation in SF mice. In marked contrast, A2A receptor deletion completely blocked these beneficial effects of L. reuteri in SF mice. Altogether, these results suggest that although absence of the adenosine A2A receptor does not affect the development of disease in SF mice, it plays a critical role in the immunomodulation by L. reuteri in Treg-deficiency disease. The adenosine A2A receptor and its activation may have a role in treating other Treg dysfunction-mediated autoimmune diseases.
Highlights
Foxp3+ regulatory T (Treg) cells play a pivotal role in the phenomenon of self-tolerance
To examine whether adenosine A2A receptor deletion alters the autoimmune damage in these tissues, we measured the area of inflammatory cell infiltration in hematoxylin and eosin (H&E)-stained tissues sections from WT, SF, A2A-/, and SF·A2A-/- mice at the 20 days of age
This study demonstrated a central role of the adenosine A2A receptor in mediating the protection of probiotic L. reuteri against inflammation in the Treg-deficient SF mouse, evidenced by the observation that SF mice with an A2A receptor deletion continued to have systemic inflammation which was unresponsive to L. reuteri treatment
Summary
Foxp3+ regulatory T (Treg) cells play a pivotal role in the phenomenon of self-tolerance. SF mice develop early-onset dermatitis, progressive multiorgan inflammation, and early death within the first month of life due to a lymphoproliferative syndrome. This lethal lymphoproliferative syndrome is predominately mediated by CD4+ T cells in humans and mice [5, 6]. The SF mouse is a valuable model for studying novel therapies for human IPEX syndrome and other autoimmune diseases associated with Treg deficiency. These include IPEX-like syndromes induced by mutations or deficiency in Itchy E3 ubiquitin protein ligase (ITCH), the α-chain of the
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